To maintain tissue homeostasis and normal functions, damaged cells need to be replaced or repaired. In mammals, such process requires extensive cell proliferation. A consequence of this massive proliferation is the accumulation of mutations, some of which may target cancer causing genes. To constrain the proliferation and survival of precancerous cells, potent tumor suppression mechanisms must be functional, one of which is senescence. Senescence limits proliferative capacity of cells, thus impeding the accumulation of multiple mutations that are necessary for tumorigenesis. Furthermore, aberrant oncogenic activation, DNA damage or oxidative stress can also activate senescence, providing a failsafe mechanism that prevents the proliferation of cells at risk for neoplastic transformation. Overcoming senescence is an essential property acquired by cancer cells. Despite its importance, the molecular regulation of senescence is poorly understood, and many of the critical regulators remain unidentified. Our long-term goal is to understand the molecular regulation of senescence and its function in tumorigenesis. We recently have identified Smurf2 as a novel regulator of senescence. Its expression is up-regulated in response to telomere shortening in human fibroblasts, and such elevated expression is sufficient to induce senescence. Our preliminary studies have found that down-regulation of Smurf2 postpones senescence in human fibroblasts, whereas mouse embryonic fibroblasts deficient in Smurf2 are immortal in culture. We hypothesize that Smurf2 regulates senescence through its ability to modulate the p16 and p21 senescence pathways, and that consequently Smurf2 might play an important role in tumorigenesis. In this proposal, we will characterize the function of Smurf2 in senescence regulation and tumorigenesis with three specific aims. In Aim 1, we will characterize the function of Smurf2 in regulation of the p16 senescence pathway. In Aim 2, we will study the mechanism by which Smurf2 regulates the p21 senescence pathway. In Aim 3, we will investigate the function of Smurf2 and its regulation of senescence in tumorigenesis. These studies will provide direct evidence for a function of Smurf2 in tumorigenesis. Furthermore, these studies will identify new genetic components in the senescence pathways, and provide new insight into how senescence is regulated, an important step towards the fulfillment of the great promise of senescence in cancer treatment. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly advance our understanding of the molecular regulation of senescence and its function in cancer. Such knowledge will have an important impact on not only the development of effective therapies targeting the senescence response and the advancement of clinical benefit utilizing such strategy for cancer treatment, but also the understanding of the relationship between cancer and aging, which is important for achieving prevention or amelioration of age-related debilitation caused by cancer.